Victor G. Chedid, MD, a gastroenterologist at the Mayo Clinic in Rochester, MN, discussed the importance of the guidelines in an interview with GI & Hepatology News.

In your opinion, what are the top three recommendations from this guideline?

Dr. Chedid:

• Early initiation of advanced therapies rather than step-up therapy or immunomodulator-only strategies for moderate to severe Crohn’s disease.

• First-line therapy in advanced-therapy–naïve patients should use higher-efficacy medications (infliximab, adalimumab, vedolizumab, ustekinumab, risankizumab, mirikizumab, guselkumab) over lower-efficacy medications (certolizumab pegol or upadacitinib).

• Although immunomodulator monotherapy is discouraged for induction of remission, combination therapy with an immunomodulator is suggested only when using infliximab in individuals naïve to thiopurines to optimize outcomes.

Are there specific recommendations in the guideline that surprised you?

Dr. Chedid: One notable aspect is the guideline’s positioning of upadacitinib. For advanced-therapy–naïve patients, it is grouped with certolizumab pegol as a lower-efficacy medication. However, for patients with prior exposure to advanced therapies, upadacitinib is considered higher efficacy, while certolizumab pegol and vedolizumab remain lower efficacy.

In October 2025, the FDA updated upadacitinib’s labeling. Previously, treatment required failure or intolerance to an anti-TNF agent. The updated labeling allows its use after inadequate response to one approved systemic therapy, provided anti-TNF therapy is clinically inadvisable.

AGA’s classification stems from three randomized controlled trials showing that upadacitinib was highly effective for isolated colonic Crohn’s disease but not significantly effective for ileal disease, leading to its lower-efficacy designation for advanced-therapy–naïve patients.

Why is now a good time for publication of this guideline? What gap(s) in knowledge or therapeutics does it seek to fill?

Dr. Chedid: The timing reflects a rapidly evolving therapeutic landscape in the management of moderate to severe Crohn’s disease. Since the last AGA guideline in 2021, four new advanced therapies have been approved, nearly doubling available treatment options. This guideline addresses the need for clear, evidence-based positioning of these novel therapies and provides strong support for moving away from traditional “step-up” strategies reliant on corticosteroids or slow-acting immunomodulators.

The guideline emphasizes early use of high-efficacy biologics and small molecules to prevent Crohn’s-related complications and improve long-term outcomes. Because the field is changing quickly, AGA developed these as living guidelines, to be reviewed and updated every 6 months so clinicians can stay aligned with emerging evidence and innovations.

What additional research may be needed? What questions remain unanswered?

Dr. Chedid: Several important questions remain regarding therapy positioning for moderate to severe Crohn’s disease:

• Combination therapies beyond infliximab plus thiopurine need further study. One area of interest is whether combining IL-23 inhibitors with JAK inhibitors provides added benefit.

• For patients naïve to anti-TNF therapy but previously exposed to other advanced therapies, it is unclear whether initiating anti-TNF therapy later offers advantages.

• More research is needed to clarify the safety profile of JAK inhibitors during pregnancy, as current practice avoids their use in individuals of childbearing age considering pregnancy.

• Evidence is still insufficient to define optimal treat-to-target goals. It remains unknown whether symptomatic remission or endoscopic healing should be prioritized. Long-term outcomes and complication risks based on these goals require further investigation.

Given the living nature of these guidelines, more changes in therapy positioning are expected as new treatments and evidence emerge.

Disclosures: Dr. Chedid serves as Principal Investigator for a Pfizer-funded study on LGBTQ+ health and IBD. He also provides consulting for Takeda on educational programs related to LGBTQ+ health and IBD, and for PRIME Education on CME activities focusing on the same.